News Analysis: U.S. Approval of Etravirine (Intelence)

On Jan. 18, the U.S. Food and Drug Administration (FDA) approved the first new non-nucleoside reverse transcriptase inhibitor (NNRTI) in nearly a decade. It was known throughout much of its development as TMC125, and is now known by its generic name, etravirine, and the brand name of Intelence. Etravirine's approval follows on the heels of the approvals of four other new antiretrovirals, making this an unprecedented time in the history of HIV/AIDS medicine.

To learn more about etravirine, and its potential impact on the treatment of HIV-infected patients, I spoke by phone with Dr. Cal Cohen, Research Director of Harvard Vanguard Medical Associates and Community Research Initiative of New England in Boston, Mass. He is also a clinical instructor at Harvard Medical School. Dr. Cohen has participated in research on etravirine, and has also received funding from Tibotec, which developed etravirine.

What kind of patient is etravirine meant for, and how do you think it will be used?

Etravirine was studied in treatment-experienced adult patients. That's where we have our information. Therefore, they are the focus of the use of this drug. It's people who have a history of using multiple classes of drugs who, despite that, are now dealing with breakthrough viremia and a history of resistance and now need to construct a new regimen. That's the group for whom etravirine is going to be an important drug.

There were a few adverse events that were picked up on in the studies. Probably the first to note is that there are some people who will have a rash with non-nucleosides in general. Overall, the incidence of rash was around 10% or so on etravirine. A small number of people did have a severe rash, the kind of rashes that we call Stevens-Johnson and refer to by other kinds of descriptions. Thankfully, severe rash was quite rare and very few people had to stop this drug due to rash. But nevertheless, that's certainly one of the more common and important side effects for clinicians to be aware of. The typical non-nuke reaction occurs in week two and fades in most patients as they stay on treatment, and that's true again for etravirine.

The only other side effect in terms of how people felt is that some people did note some nausea. Otherwise, there really wasn't too much else that was picked up on in terms of the kind of side effects we talk about. In terms of lab tests, the drug also looked pretty clean. There was really only a small percentage of patients who differed from those on placebo on a number of lab tests.

Could you summarize the DUET1,2 studies, which were the basis for the approval of etravirine?

The DUET studies were randomized trials -- two very large trials of essentially the same design. Triple-class-experienced patients who were viremic despite prior treatment were randomized to receive a new regimen either with or without etravirine. The new regimen that they were given always included darunavir [TMC114, Prezista], one of the newer antiretrovirals; the rest of the regimen was left to the discretion of the local investigator, although they certainly could not have any other non-nucleoside in that regimen. The only randomization then was with regards to how much difference did etravirine make to that background regimen.

In the DUET data what we have are week 24 data. At this point this study is, in fact, still ongoing, but the data clearly demonstrate the importance of etravirine to an optimized background regimen, even one containing darunavir. On average, there was about a 50% increase in the response rate, meaning that if the average response rate of patients getting to less than 50 was about 40% of those enrolled, with etravirine we are up to about 60%.

Equally important is to understand how much difference the optimized background could make. In fact, when we looked at a truly optimized background, one containing darunavir and etravirine and enfuvirtide [T-20, Fuzeon], in other words three reasonably active drugs -- particularly in the subset for whom etravirine was active by resistance testing -- then over 80% of patients achieved a viral load of less than 50 copies, which is a clear illustration of how this drug in combination will increase the odds of virologic suppression.

How does that compare with other new drugs that were recently approved for this population?

It's of course hard to compare across trials because patients are different, there are different enrollments, and there are different amounts of baseline resistance. But it's fair to say that this is similar to the kinds of advances we make when we add a new drug. We see a clear illustration of an increased rate of virologic suppression. And the more the regimen is active, the larger the number of people who can get to less than 50. That's what we see here one more time.

I understand that etravirine has only been studied with one protease inhibitor, darunavir. We have limited data about its use with other protease inhibitors.

Well, we have some pharmacokinetic data for etravirine together with other protease inhibitors, but you're absolutely right. The DUET studies of etravirine were in combination with darunavir, so that's where we have the vast majority of our data. However, we do have some cautions about not using etravirine with a couple of other protease inhibitors due to some drug interactions. Tipranavir [Aptivus] dramatically decreases the levels of etravirine. And there are some other drug interactions, like with atazanavir [Reyataz]. You actually double your exposure to the etravirine in the presence of atazanavir. Because it's reasonably complicated, clinicians who are going to use this drug should be comfortable with the package insert and the pharmacokinetic data. [Click here to view the package insert (PDF).] But the short answer is that right now we have the most data with etravirine and darunavir. That's certainly a solid combination for the kind of patients who this drug is useful for.

Are there any other notable drug-drug interactions? I'm thinking about statins, hormonal contraceptives, methadone [Dolophine, Methadose] and antidepressants.

All important drugs. And again, instead of going through an entire list and having listeners try to memorize it, all of this is captured in the package insert. There are a couple of things, just notable. For example, with a drug like atorvastatin [Lipitor], there isn't too much of a problem. There are some commonly used drugs like methadone, for example, where we don't expect any important drug-drug interactions. With oral contraceptives we don't expect any important drug-drug interactions. Some of the tuberculosis drugs and seizure drugs are commonly a problem for many of the non-nucleosides, and that's again true here. But the list in the package insert is actually pretty clear, and goes through which drugs to be careful with.

Is it known how many mutations, and which mutations, will cause etravirine to fail?

There's actually a fair bit of analysis to help clinicians and guide us. As the company presented for years, and the FDA agreed, fortunately, the K103N mutation, the signature mutation that arises on efavirenz [Sustiva, Stocrin], does not impact the activity of etravirine. That's one piece of reassuring news. But to make it simple, they certainly have a list of NNRTI mutations that are relevant to all NNRTIs. Probably the simplest thing to take as a take home is that the more NNRTI mutations there were, the less activity of etravirine. Again, with the exclusion of K103N, as I mentioned earlier. It's fair to say that this drug will be good for people with a few NNRTI mutations, and compromised for people with a lot of NNRTI mutations.

Are there any looming questions about etravirine that you would like to see addressed in the near future? I know, for instance, that only 10% of the study participants were women. Is that a problem or an open question?

Well, it certainly suggests we have limited experience in women. You're absolutely right. Although it's fair to point out that there were 600 people in the studies, so 10% of that gives us at least some information to start out with. In addition, there were a few thousand people in the expanded access protocols. Hopefully, over time, we'll get additional information about different types of populations. One piece of information that might be useful for clinicians and patients is that this drug is not renally cleared. People who have compromised renal function don't have to worry about dose adjusting. This drug is hepatically cleared, so there's no worry about serum creatinine or their creatinine clearance.

I noticed in the approval from the FDA that etravirine has to be taken with a meal, and if it's not taken with at least 350 calories, its levels can fall a dramatic 50%. Can you talk about this and other cautions with regards to this drug?

There are a number of drugs that have food effects, in which food is important to take with these drugs. This drug is in that category, in that it does require some food. The good news is that it doesn't really matter what type of food. They studied a range of meals. As you point out, with as little as 350 calories -- although much larger meals were also studied -- the drug was well absorbed over that range of meals. The only real caution is to not take this drug on an empty stomach. Other than that, though, there are no particular cautions about how to take it. It's taken twice a day. It doesn't have to be taken precisely every 12 hours. It actually has a reasonable half-life, so it's got that nice cushion. Other than that meal effect, there really isn't much else in terms of taking the drug. Otherwise, it's pretty standard.

What sort of half-life does it have?

The half-life that's listed on the label is 41 hours, although there's quite a range, with plus or minus 20 hours. But what, overall, that suggests is that the vast majority of people will have a long exposure to this drug after each dose.

I noticed that the pills seem to dissolve pretty quickly and that they should be swallowed pretty quickly because of that.

That certainly makes sense, although in the studies I have not heard any descriptions of people having trouble swallowing the tablets. But you're right, one of the things that Tibotec did was to provide advice for people who couldn't swallow the tablets. What they're instructed to do is put it in a glass of water, create a slurry and just drink it. And then, of course, make sure to get any little tablet pieces remaining in the glass by adding additional water. But other than that, there haven't been any cautions about swallowing it quickly or dissolving it in the mouth, although it certainly makes sense to think about that. We haven't heard about that much in the studies, however.

I understand that Tibotec has worked closely with the HIV activist community on pricing and other issues, and that the pricing of etravirine is lower than that of other recently approved drugs for rescue therapy by several dollars a day. Can you comment? Is that an issue for patients in general, the pricing of the drugs in the United States?

I actually don't know. I have not heard the actual price and I know that there are several ways that the price can be altered depending on what deals different insurance companies make. But I guess overall that I would say it's good news that the drug was less expensive than other recently approved drugs. It certainly increases the likelihood of making sure we will get access to this in a broad range of insurances. Needless to say, it ultimately comes down to making sure that every insurance company, including the public assistance programs, makes this drug available to the people and I think there's very little controversy that the drug at this price is an important contribution to the field.

With the approval of five new antiretrovirals in two years, all geared for treatment-experienced patients, do you think HIV specialists feel confident about building an HIV regimen with so many new agents?

Certainly there are a couple of key pieces that are needed to construct new regimens. The first, as you mentioned, is new drugs that are active against these viruses. So now we have an extraordinary repertoire of drugs approved in the past year, something we really haven't had in the history of our field. Having several new classes and several new drugs in existing classes is a new opportunity.

However, it's also fair to say that we haven't studied every combination of these drugs. So clinicians will frequently be wondering: What is the best combination? Is it three drugs, or should I give a fourth? Which is the best combination? Needless to say, there are going to be a lot of questions and some answers. We have some information to guide us. Clinicians can certainly look to each other. There are lots of ways in which clinicians can stay educated. There are lots of ways for patients to stay appraised. We are still learning, however, the best ways to make sure these drugs lead to a good response.

So I guess, look forward to more conferences and more presentations.

Yes. There are certainly some basic principles, no doubt. The more active drugs you have, the more likely you are to get that viral load under control. That's the easy part. The more subtle part is where we are going to need more guidance. What would we do with etravirine if there are one or two mutations and the protease inhibitor is a little compromised? Do I need etravirine and should I add maraviroc [Selzentry, Celsentri]? Are three drugs enough? All of those kinds of questions. Do I add nucleosides? Should it be six drugs? There are always going to be these kinds of questions. That's why research is still going to be needed in our field for years to come.

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